Avatars to help tailor glioblastoma treatments

Glioblastoma is an aggressive and difficult to treat brain tumor in adults. On average, patients survive only 1.5 years. The standard of care for this disease, which includes surgery followed by radiation and chemotherapy, has not changed in 18 years. This is partly because cancer is highly variable, with many differences among patient populations. Second, these cancer cells also sneakily trick the body: They even recruit immune cells called macrophages to help them. Third, they are inaccessible to most anti-cancer drugs, which have only limited ability to penetrate brain tissues. Besides standard-of-care treatment, oncologists are testing medications on glioblastoma patients with no guarantee that they will work, often accompanied by negative side effects.

“These patients really need new treatments,” said Professor Holger Gerhardt, senior author of the study and Deputy Scientific Director of the Max Delbrück Center in Berlin. says. "It is very important to identify patients who do and do not respond to a particular treatment."

Lead author and cancer researcher Lise Finotto at the VIB-KU Leuven Center for Cancer Biology in Belgium and previously at the Max Delbrück Center, and her senior collaborators Gerhardt and Professor Frederik De Smet from KU Leuven, created a screening platform. can be developed to find new targets for drugs against glioblastoma. It can also be used to check whether a particular patient will respond to treatment. Study "EMBO Molecular Medicine" It was published in the magazine.

To understand how macrophages might interact with glioblastoma cells from different patients, researchers created zebrafish "avatars." they created. Gerhardt's laboratory works extensively with zebrafish. These three-centimeter-long fish are considered good model organisms because their embryos are translucent, making it possible to watch what's going on inside.

An unexpected survival

Finotto studied glioblastoma stem cells from seven patients collected by scientists in the De Smet laboratory, which had established a living tissue bank of glioblastoma samples. By injecting these into zebrafish embryos, he created xenograft models, an avatar for each patient. When he imaged the embryos live, it became clear that the glioblastoma cells adapted well to their new environment. He found that the zebrafish's immune system sent macrophages as part of the immune response to control the tumor. However, as is typical in glioblastoma, macrophages were suppressed. Tumors have various mechanisms to reprogram macrophages to help them grow.

Finotto said, "We wanted to learn how to turn macrophages into a tumor-attacking state." says. And a clue emerged when they noticed that a patient's tumor did not suppress the normal macrophage response.

De Smet from KU Leuven said, "After examining the medical details more closely, this patient was considered a 'long-term survivor.' "We discovered that he is who we say he is." says. "This is the term used for patients with glioblastoma, an extremely rare form of brain cancer, whose survival is more than five years."

Test platform

Finotto says their curiosity about the patient is the driving force behind the project. When they cultured tumor cells and macrophages together and performed single-cell RNA sequencing, they learned that the LGALS1 gene was downregulated in the long-term survivor's tumor compared to the others. Previous studies have also shown that silencing LGALS1 in glioblastoma cells may result in longer survival.

Scientists confirmed their results by knocking out the gene in another patient's sample and observed that the tumor became less invasive in zebrafish models.

Finotto says this platform can be used to identify promising targets other than LGALS1 in the treatment of glioblastoma. And with some refinement, zebrafish avatars can be used to determine which treatments will work. Gerhardt says researchers may be able to find the cells that cause tumor regression by investigating whether tumor cells from specific patients inoculated into zebrafish respond when treated with various drugs.

De Smet said, "Equipped with this information, we can inform oncologists and help them make more supported treatment decisions for the patient." he says.